More immunosuppressive, more immunotherapy responsive? A double-edged sword of HBV-induced immune response in HCC
Authors: Chien-Hao Huang, Sen-Yung Hsieh
Journal: Hepatology (2023)

BACKGROUND Chronic HBV infection is the leading cause of HCC, particularly in Asia and Africa. Despite demonstrating response rates ranging from 15% to 30% in patients with HCC, immune checkpoint inhibitor (ICI) immunotherapy has not achieved the optimal efficacy as observed in melanoma.1 Recent studies reveal that immunotherapies may be more effective in viral etiologies, particularly HBV, than nonviral HCC,2,3 while there is no difference related to the etiology of HCC in patients receiving tyrosine-kinase inhibitor therapy.2 These findings suggest the profound implication of the tumor microenvironment (TME) in response to immunotherapies. It is thus intriguing to ask why HBV+-HCC has a better response to ICI therapy, what are the roles of HBV-specific immune cells in modulating the debilitated immune in HCC, and whether it is possible to revive the HBV-related immune for anticancer therapy. Does HBV-specific immune sculpture the immune in TME of HCC? Multi-omics studies, including single-cell RNA sequencing, cytometry by time-of-flight, and multiplexed immunohistochemistry, have shown that the TME of HBV+-HCC is immune hot but highly immunosuppressive characterized by the enrichment of exhausted CD8+ T cells, regulatory T cells (Treg), and HBV-specific CD8+ T cells recognizing diverse HBV-derived epitopes, including tissue-resident memory T cells (TRM).4,5 In addition, Treg and TRM from HBV+-HCC express more PD-1 and are functionally immune suppressive and exhausted than nonviral HCC. Clinically, Treg cells in the TME were associated with a poor prognosis, while HBV-specific TRM cells were associated with a good prognosis in HCC.4,5 Together, these studies suggest that chronic HBV infection usually sculptures a hot but debilitated immune status favoring tumor development in the liver. How chronic HBV infection modulates immune profiles in the TME of HCC? You et al6 combined epigenomic and transcriptomic approaches to delineate the HBV-specific Treg, CD8+ exhausted T cells (Tex), and HBV-specific effector memory CD8 T cells and characterized their T-cell receptor repertoire clonality and specificity in a cohort of 43 patients with HBV+-HCC and 11 patients with HBV--HCC. They found a shared epigenomic program that regulates the differentiation of HBV-specific Treg and Tex and the HBV-related Treg-CTLA4 and CD8+Tex-TOX subsets in the TME of HCC. Meanwhile, a significant proportion of HBV-specific effector memory CD8 T cells and HBV-related FGFBP2+ CD8+ T cells were governed by shared transcription factor motifs of AP1, NFE2, and BACH1/2,6 suggesting the role of chronic HBV infection in sculpturing the immune profile of TME (Figure 1).FIGURE 1: The epigenomic programs leash and unleash the HBV-associated immune for tumor development and antitumor immunotherapy, respectively. Created with BioRender.com. Abbreviations: ICI, immune checkpoint inhibitor; TCR, T-cell receptor; TME, tumor microenvironment; Treg, regulatory T cells.Can we reinvigorate the HBV-induced immune from debilitation to empowered anti-tumor immunity? Clinically, Treg cells in the TME were associated with a poor prognosis, while HBV-specific TRM cells were associated with a good prognosis in HCC.4,5 Furthermore, HBV-specific CD8+T cells expressed FASLG, linked to the FASLG-FAS cell-to-cell communication network involving HBV-specific Treg cells and tumor cells.6 These findings hold substantial implications for targeting immunosuppressive cells like HBV-related Treg in TME to improve the efficacy of immunotherapy. Indeed, a recent study shows the treatment with a CCR4 antagonist blocked intratumoral Treg accumulation, overcame sorafenib resistance, rescued CD8+ T-cell function, and sensitized tumors to PD-1 checkpoint blockade in HBV+-HCC.7 In contrast, the anti-PD1 treatment led to an increase in the number and size of tumor nodules, which correlated with increased hepatic CD8+PD1+TOX+ T cells in NASH-HCC.3 These phenomena may partially explain why ICI therapy is more effective in patients with HBV+-HCC than in those with HBV−-HCC. Future challenges The discovery by You et al6 sheds light on the potential for virus-specific T cells to serve as elicitors of anti-tumor immunity in viral-associated HCC. However, the discrepancies in ICI responsiveness between HBV+-HCC and HCV+-HCC has not been fully explained. In recent years, more and more patients with chronic hepatitis B have achieved clinical HBV cured (HBsAg seroclearance), particularly after a finite nucleos(t)ide analog therapy.8 For these patients, it is unclear whether the "epigenetic scar" seen in patients cured of chronic hepatitis C9,10 is also present. As such, how are the potential impacts of the HBV-specific immune on immunotherapies of HCC in patients with HBsAg seroclearance? Nevertheless, reanimating the long-term infection-induced exhausted immune cells to treat virus-related cancers provides a promising paradigm for developing targeted immunotherapies.